Pterostilbene cocrystals

ABSTRACT

Cocrystals of pterostilbene are disclosed, including: pterostilbene:caffeine cocrystal, pterostilbene:carbamazepine cocrystal, pterostilbene:glutaric acid cocrystal, and pterostilbene:piperazine cocrystal. The pterostilbene:caffeine cocrystal is polymorphic. Forms I and II of the pterostilbene:caffeine cocrystal are disclosed. The therapeutic uses of the pterostilbene cocrystals and of pharmaceutical/nutraceutical compositions containing them are also disclosed. The disclosure sets out various methods of making and characterizing the pterostilbene cocrystals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to and claims priority to U.S. ProvisionalApplication 61/301,001, entitled “Nutraceutical Cocrystals: UtilizingPterostilbene As A Cocrystal Former,” filed Feb. 3, 2010, and U.S.Provisional Application 61/301,029, entitled “Pterostilbene Cocrystals,”filed Feb. 3, 2010, the contents of which are incorporated in theirentirety herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to new crystalline compounds containingpterostilbene, more particularly, the invention relates to pterostilbenecocrystals, therapeutic uses of those pterostilbene cocrystals, andpharmaceutical/nutraceutical compositions containing them.

2. Description of Related Art

Pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) is a naturallyoccurring stilbenoid compound, and a non-ionizable methylated structuralanalog of resveratrol. The chemical structures of pterostilbene andresveratrol are:

Pterostilbene has been characterized as a nutraceutical, being found innature in a number of tree barks and a variety of berries, includinggrapes, as well as plants commonly used in traditional folk medicine.Both resveratrol and pterostilbene have been reported to exhibit a rangeof biological activities including anti-cancer, antioxidant,anti-inflammatory and other potential health benefits. A number of invitro and in vivo studies of pterostilbene have been conducted in whichit demonstrated cytotoxic activity against cancer cell lines in vitroand decreased plasma glucose levels by 42% in hyperglycemic rats(comparable to the commercially available drug, metformin, which reducesglucose levels by 48%). Additionally, the LDL/HDL cholesterol ratio wassignificantly lowered in hypercholesterolemic hamsters that were fed 25ppm pterostilbene in their diet compared to the control animals. The useof pterostilbene to ameliorate oxidative stress and improve workingmemory and compositions containing pterostilbene are described inpublished U.S. application 2009/0069444, which is incorporated herein byreference. Significant interest in pterostilbene has therefore beengenerated in recent years due to its perceived health benefits, leadingto increased consumption of foods that contain the compound, such asgrapes and berries.

A number of pharmacological studies have been conducted onpterostilbene; but, very little investigation on the behavior ofpterostilbene in the solid state has appeared in the open literature,and thus its solid-state properties appear not to have been thoroughlystudied to date.

Pterostilbene has been noted to have poor solubility in water, making itdifficult to incorporate in food extracts or supplements (Lopez-Nicolas,J. M.; Rodriguez-Bonilla, P.; Mendez-Cazorla, L.; Garcia-Carmona, F.,Physicochemical Study of the Complexation of Pterostilbene by Naturaland Modified Cyclodextrins. Journal of Agricultural and Food Chemistry2009, 57, (12), 5294-5300.). In addition, pterostilbene exhibits poorbioavailability and is easily oxidized by various enzymes (Pezet, R.,Purification and characterization of a 32-kDa laccase-like stilbeneoxidase produced by Botrytis cinerea. FEMS Micobiology Letters 1998,167, 203-208 and Breuil, A. C.; Jeandet, P.; Adrian, M.; Chopin, F.;Pirio, N.; Meunier, P.; Bessis, R., Characterization of a pterostilbenedehydrodimer produced by laccase of Botrytis cinerea. Phytopathology1999, 89, (298-302).). The melting point has been reported as 82° C.(Mallavadhani, U. V.; Sahu, G., Pterostilbene: A Highly ReliableQuality-Control Marker for the Ayurvedic Antidiabetic Plant ‘Bijasaf’.Chromatographia 2003, 58, 307-312.) Efforts to improve the solubility ofpterostilbene have focused on formulation approaches such as by usingcyclodextrins (Lopez-Nicolas 2009).

Polymorphic forms of pterostilbene have recently been reported. Fivepolymorphs of pterostilbene are disclosed in PCT/US2010/22285, filedJan. 27, 2010, which is incorporated herein by reference.

Due to the development of the drug discovery strategy over the last 20years, physicochemical properties of drug development candidates havechanged significantly. The term “drug” as used herein is also meant toinclude nutraceuticals and active nutraceutical ingredients, even thoughnutraceuticals are not subject to regulatory trials and approval. Thedevelopment candidates are generally more lipophilic and less watersoluble, which creates huge problems for the industry. Research hasshown that some drug candidates fail in the clinical phase due to poorhuman bioavailability and/or problems with their formulation.Traditional methods to address these problems, without completelyredesigning the molecule, include salt selection, producing amorphousmaterial, particle size reduction, prodrugs, and different formulationapproaches.

Although therapeutic or clinical efficacy is the primary concern for adrug (or an active nutraceutical ingredient), the salt and solid-stateform (i.e., the crystalline or amorphous form) of a drug candidate canbe critical to its pharmacological properties and to its development asa viable drug. Crystalline forms of drugs have been used to alter thephysicochemical properties of a particular drug. Each crystalline formof a drug candidate can have different solid-state (physical andchemical) properties which may be relevant for drug delivery.Crystalline forms often have better chemical and physical propertiesthan corresponding non-crystalline forms such as the amorphous form. Thedifferences in physical properties exhibited by a novel solid form of adrug (such as a cocrystal or polymorph of the original drug) affectpharmaceutical parameters such as storage stability, compressibility anddensity (relevant for formulation and product manufacturing), anddissolution rates and solubility (relevant factors in achieving suitablebioavailability).

Dissolution rates of an active ingredient in vivo (e.g., gastric orintestinal fluid) may have therapeutic consequences since it affects therate at which an orally administered active ingredient may reach thepatient's bloodstream. In addition, solubility, a thermodynamicquantity, is a relevant property in evaluating drug delivery because apoorly soluble crystalline form of a drug will deliver less drug than amore soluble one in the same formulation.

Because these practical physical properties are influenced by thesolid-state properties of the crystalline form of the drug, they cansignificantly impact the selection of a compound as a drug, the ultimatepharmaceutical dosage form, the optimization of manufacturing processes,and absorption in the body. Moreover, finding the most adequate solidstate form for further drug development can reduce the time and the costof that development.

Obtaining suitable crystalline forms of a drug is a necessary stage formany orally available drugs. Suitable crystalline forms possess thedesired properties of a particular drug. Such suitable crystalline formsmay be obtained by forming a cocrystal between the drug and a coformer.Cocrystals often possess more favorable pharmaceutical andpharmacological properties or may be easier to process than known formsof the drug itself. For example, a cocrystal may have differentdissolution and solubility properties than the drug. Further, cocrystalsmay be used as a convenient vehicle for drug delivery, and new drugformulations comprising cocrystals of a given drug may have superiorproperties, such as solubility, dissolution, hygroscopicity, and storagestability over existing formulations of the drug.

To the best of the joint inventors' knowledge, no cocrystals ofpterostilbene have been reported in the open/academic or patentliterature. In fact, the field of nutraceutical cocrystals appears to bea relatively unexplored landscape.

A cocrystal of a drug (an active nutraceutical ingredient or an activepharmaceutical ingredient) is a distinct chemical composition betweenthe drug and coformer, and generally possesses distinct crystallographicand spectroscopic properties when compared to those of the drug andcoformer individually. Unlike salts, which possess a neutral net charge,but which are comprised of charge-balanced components, cocrystals arecomprised of neutral species. Thus, unlike a salt, one cannot determinethe stoichiometry of a cocrystal based on charge balance. Indeed, onecan often obtain cocrystals having stoichiometric ratios of drug tocoformer of greater than or less than 1:1. The stoichiometric ratio ofan API to coformer is a generally unpredictable feature of a cocrystal.

Without limiting the present invention to any particular definitionalconstruct because others may define the term differently, the term“cocrystals” may be thought of as multi-component crystals composed ofneutral molecules. These multi-component assemblies are continuing toexcite and find usefulness, particularly within the pharmaceuticalarena, for their ability to alter physicochemical properties. Morespecifically, cocrystals have been reported to alter aqueous solubilityand/or dissolution rates, increase stability with respect to relativehumidity, and improve bioavailability of active pharmaceuticalingredients.

A necessary consideration when designing cocrystals, if the end goal isa potential marketed drug-product, is incorporating a suitable cocrystalformer (coformer) with an acceptable toxicity profile. Within thepharmaceutical industry, coformers are typically selected from the samelist of pharmaceutically accepted salt formers, generally regarded assafe (GRAS) and/or everything added to food in the United States (EAFUS)lists, due to previous occurrence of these molecules in FDA approveddrug or food products. An additional group of molecules to be consideredas possible coformers are the naturally occurring compounds,nutraceuticals.

A nutraceutical (portmanteau of nutrition and pharmaceutical) compoundis defined as, “a food (or part of a food) that provides medical orhealth benefits, including the prevention and/or treatment of a diseaseand possesses a physiological benefit or reduces the risk of chronicdisease”. Utilizing naturally occurring compounds as coformers givesextension to the list of potential molecules accessible to thepharmaceutical industry and provides additional physiological benefitsto the consumer.

In some circumstances, such as with cocrystals of carboxylic acids, thecoformer is generally viewed as the acid moiety whereas the compoundwhose therapeutic properties are of interest is viewed as the drug, asin the case of the pterostilbene:glutaric acid cocrystal. In othercircumstances, more than one component may be viewed as the drug. In thecase of the pterostilbene cocrystals reported herein, one may viewpterostilbene as acting as a drug and carbamazepine as a coformer or thereverse. Likewise, one may view the pterostilbene in thepterostilbene:caffeine cocrystal as a drug and the caffeine as acoformer or the reverse. However, regardless of what label is used for aparticular component, the cocrystal structure is not altered. Forpurposes of the invention reported herein, pterostilbene is viewed asthe drug whereas the second component of each of the cocrystals isviewed as the coformer.

In a cocrystal, the drug and the coformers each possess unique latticepositions within the unit cell of the crystal lattice. Crystallographicand spectroscopic properties of cocrystals can be analyzed as with othercrystalline forms such as with X-ray powder diffraction (XRPD), singlecrystal X-ray crystallography, and solid state NMR, among othertechniques. Cocrystals often also exhibit distinct thermal behaviorcompared with other forms of the corresponding drug. Thermal behaviormay be analyzed by such techniques as capillary melting point,thermogravimetric analysis (TGA), and differential scanning calorimetry(DSC) to name a few. These techniques can be used to identify andcharacterize the cocrystals.

SUMMARY OF THE INVENTION

The present invention relates to the following novel pterostilbenecocrystals:

(1) pterostilbene:caffeine (“cocrystal 1”);

(2) pterostilbene:carbamazepine (“cocrystal 2”);

(3) pterostilbene:glutaric acid (“cocrystal 3”); and

(4) pterostilbene:piperazine (“cocrystal 4”).

The molecular structures of pterostilbene, caffeine, carbamazepine,glutaric acid, and piperazine (left-to-right) are shown below:

For each cocrystal, the single crystal structures were determined andseveral physical properties were measured.

The pterostilbene:caffeine cocrystal is polymorphic.

Cocrystals were prepared having a 1:1 stoichiometric molar ratio ofpterostilbene with caffeine (two polymorphs, Form I and Form II).

Cocrystals were prepared and characterized by crystallographic (XRPD,single-crystal) and thermoanalytical (TGA, DSC) techniques, amongothers.

Physical stability of the cocrystals with respect to relative humidity(RH) was examined and found to be dramatically improved, in some cases,in relationship to, for example, caffeine or carbamazepine.

The pterostilbene:carbamazepine cocrystal was stable upon slurrying inwater for three days; therefore, aqueous equilibrium solubilitymeasurements were carried out, revealing that the cocrystal solubilitywas 7× lower than carbamazepine dihydrate and 2.5× lower thanpterostilbene.

Slurring the pterostilbene:caffeine cocrystal Form I in water led to asolution that was supersaturated with respect to pterostilbene,resulting in the precipitation of pterostilbene after three days;therefore concentrations at specific time points were measured asopposed to equilibrium solubility. At five hours the concentration ofthe caffeine cocrystal was 33× lower than the caffeine hydratesolubility, but was 27× higher than the pterostilbene solubility.

Slurring the pterostilbene:piperazine cocrystal in water led to asolution that was supersaturated with respect to pterostilbene,resulting in the precipitation of pterostilbene after three days;therefore concentrations at specific time points were measured. At fivehours the concentration of the pterostilbene:piperazine cocrystalrevealed a 6× increase in comparison to the solubility of pterostilbene.

Other properties of the cocrystals were also characterized.

As noted above, the present invention also relates to Forms I and II ofthe pterostilbene:caffeine cocrystal 1.

The invention further relates to therapeutic uses of those pterostilbenecocrystals, and pharmaceutical/nutraceutical compositions containingthem.

Methods of making the pterostilbene cocrystals are a further aspect ofthe invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows juxtaposed XRPD patterns for pterostilbene (Form I),caffeine, carbamazepine, a cocrystals 1 (Form I and II) and 2.

FIG. 2 shows the XRPD pattern of pterostilbene:caffeine cocrystal 1(Form I).

FIG. 3 shows the DSC and TGA traces of pterostilbene:caffeine cocrystal1 (Form I).

FIG. 4 shows an ORTEP drawing of the single-crystal X-ray structure ofpterostilbene:caffeine cocrystal 1 (Form I).

FIG. 5A shows a top-view of the two-dimensional sheet of cocrystal 1,displaying the rows of caffeine and pterostilbene.

FIG. 5B shows a side-view of the relatively planar, stackedtwo-dimensional sheets of FIG. 5A.

FIG. 6 shows the XRPD pattern of pterostilbene:caffeine cocrystal 1(Form II).

FIG. 7 shows the DSC and TGA traces of pterostilbene:caffeine cocrystal1 (Form II).

FIG. 8 shows an ORTEP drawing of the single-crystal X-ray structure ofpterostilbene:caffeine cocrystal 1 (Form II).

FIG. 9 shows the XRPD pattern of pterostilbene:carbamazepine cocrystal2.

FIG. 10 shows the DSC and TGA traces of pterostilbene:carbamazepinecocrystal 2.

FIG. 11 shows an ORTEP drawing of the single-crystal X-ray structure ofpterostilbene:carbamazepine cocrystal 2.

FIG. 12A shows a four-component supermolecule of cocrystal 2.

FIG. 12B shows a side-view of “translational stacked” carbamazepinedimers of cocrystal 2.

FIG. 13 shows the XRPD pattern of pterostilbene:glutaric acid cocrystal3.

FIG. 14 shows an ORTEP drawing of the single-crystal X-ray structure ofpterostilbene:glutaric acid cocrystal 3.

FIG. 15 shows the solid state ¹³C NMR spectrum of pterostilbene:glutaricacid cocrystal 3.

FIG. 16 shows the solid state ¹³C NMR spectrum of pterostilbene.

FIG. 17 shows the solid state ¹³C NMR spectrum of glutaric acid.

FIG. 18 shows the XRPD pattern of pterostilbene:piperazine cocrystal 4.

FIG. 19 shows the DSC and TGA traces of pterostilbene:piperazinecocrystal 4.

FIG. 20 shows an ORTEP drawing of the structure ofpterostilbene:piperazine cocrystal 4.

FIG. 21 shows a concentration vs. time profile for cocrystal 1 andequilibrium solubility of pterostilbene at ambient temperatures.

FIG. 22 shows a concentration vs. time profile for cocrystal 4 andequilibrium solubility of pterostilbene at ambient temperatures.

DETAILED DESCRIPTION OF THE INVENTION

Several preferred embodiments of the present invention are described forillustrative purposes, it being understood that the invention may beembodied in other forms not specifically shown in the drawing ordescribed below.

The invention relates to novel pterostilbene cocrystals:pterostilbene:caffeine cocrystal 1, pterostilbene:carbamazepinecocrystal 2, pterostilbene:glutaric acid cocrystal 3, andpterostilbene:piperazine cocrystal 4. The pterostilbene:caffeinecocrystal is polymorphic. The invention also relates to Forms I and IIof the pterostilbene:caffeine cocrystal 1. Cocrystals 1, 2, and 3 have a1:1 molar ratio of pterostilbene to the respective coformer, while 4 hasa 2:1 molar ratio. The preparation and characterization of eachcocrystal is described in the examples below.

Other embodiments of the invention include compositions containing oneor more solid forms of the pterostilbene cocrystals such aspharmaceutical or nutraceutical dosage forms. Such pharmaceutical dosageforms may include one or more excipients, including, without limitation,binders, fillers, lubricants, emulsifiers, suspending agents,sweeteners, flavorings, preservatives, buffers, wetting agents,disintegrants, effervescent agents, and other conventional excipientsand additives. The compositions of the invention can thus include anyone or a combination of the following: a pharmaceutically acceptablecarrier or excipient; other medicinal agent(s); pharmaceutical agent(s);adjuvants; buffers; preservatives; diluents; and various otherpharmaceutical additives and agents known to those skilled in the art.These additional formulation additives and agents will often bebiologically inactive and can be administered to humans without causingdeleterious side effects or interactions.

Suitable additives may include, but are not limited to, microcrystallinecellulose, lactose, sucrose, fructose, glucose, dextrose, other sugars,di-basic calcium phosphate, calcium sulfate, cellulose, methylcellulose,cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol,sorbitol, other sugar alcohols, dry starch, dextrin, maltodextrin, otherpolysaccharides, or mixtures thereof.

In one embodiment of the present invention the solid-state pterostilbenecocrystal dosage is an oral dosage form. Exemplary oral dosage forms foruse in the present disclosure include tablets, capsules, powders,suspensions, and lozenges, which may be prepared by any conventionalmethod of preparing pharmaceutical oral dosage forms. Oral dosage forms,such as tablets, may contain one or more of the conventional,pharmaceutically acceptable additional formulation ingredients,including but not limited to, release modifying agents, glidants,compression aides, disintegrants, effervescent agents, lubricants,binders, diluents, flavors, flavor enhancers, sweeteners, andpreservatives. Tablet dosage forms may be partially or fully coated,sub-coated, uncoated, and may include channeling agents. The ingredientsare selected from a wide variety of excipients known in thepharmaceutical formulation art. Depending on the desired properties ofthe oral dosage form, any number of ingredients may be selected alone orin combination for their known use in preparing such dosage forms astablets.

Pterostilbene, an antioxidant, is known to be beneficial for humanhealth. The invention also provides therapeutic uses of thepterostilbene cocrystals and methods for delivering them, and dosageforms containing them, to humans. The dosage forms may be administeredusing any amount, any form of pharmaceutical composition and any routeof administration effective for the treatment. After formulation with anappropriate pharmaceutically acceptable carrier in a desired dosage, asknown by those of skill in the art, the pharmaceutical compositions ofthis disclosure can be administered to humans and other animals orally,rectally, parenterally, intravenously, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),bucally, as an oral or nasal spray, or the like, depending on thelocation and severity of the condition being treated. In one embodimentof the disclosure, the method of delivery is with an oral dosage form.

In certain embodiments, solid forms containing a pterostilbene cocrystalof the invention may be administered at pterostilbene dosage levels ofabout 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weightper day, one or more times a day, to obtain the desired effect. It willalso be appreciated that dosages smaller than 0.001 mg/kg or greaterthan 50 mg/kg (for example 50-100 mg/kg) can be administered to asubject in need thereof.

Coformers that may be used with pterostilbene according to the presentinvention may include, but are not limited to, any one or more of thefollowing active pharmaceutical ingredients: analgesic andanti-inflammatory drugs (NSAIDs, fentanyl, indomethacin, ibuprofen,ketoprofen, nabumetone, paracetamol, piroxicam, tramadol, COX-2inhibitors such as celecoxib and rofecoxib); anti-arrhythmic drugs(procainamide, quinidine, verapamil); antibacterial and antiprotozoalagents (amoxicillin, ampicillin, benzathine penicillin,benzylpenicillin, cefaclor, cefadroxil, cefprozil, cefuroxime axetil,cephalexin, chloramphenicol, chloroquine, ciprofloxacin, clarithromycin,clavulanic acid, clindamycin, doxyxycline, erythromycin, flucloxacillinsodium, halofantrine, isoniazid, kanamycin sulphate, lincomycin,mefloquine, minocycline, nafcillin sodium, nalidixic acid, neomycin,nortloxacin, ofloxacin, oxacillin, phenoxymethyl-penicillin potassium,pyrimethamine-sulfadoxime, streptomycin); anti-coagulants (warfarin);antidepressants (amitriptyline, amoxapine, butriptyline, clomipramine,desipramine, dothiepin, doxepin, fluoxetine, reboxetine, amineptine,selegiline, gepirone, imipramine, lithium carbonate, mianserin,milnacipran, nortriptyline, paroxetine, sertraline;3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one);anti-diabetic drugs (glibenclamide, metformin); anti-epileptic drugs(carbamazepine, clonazepam, ethosuximide, gabapentin, lamotrigine,levetiracetam, phenobarbitone, phenytoin, primidone, tiagabine,topiramate, valpromide, vigabatrin); antifungal agents (amphotericin,clotrimazole, econazole, fluconazole, flucytosine, griseofulvin,itraconazole, ketoconazole, miconazole nitrate, nystatin, terbinafine,voriconazole); antihistamines (astemizole, cinnarizine, cyproheptadine,decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine,loratadine, norastemizole, oxatomide, promethazine, terfenadine);anti-hypertensive drugs (captopril, enalapril, ketanserin, lisinopril,minoxidil, prazosin, ramipril, reserpine, terazosin); anti-muscarinicagents (atropine sulphate, hyoscine); antineoplastic agents andantimetabolites (platinum compounds, such as cisplatin, carboplatin;taxanes, such as paclitaxel, docetaxel; tecans, such as camptothecin,irinotecan, topotecan; vinca alkaloids, such as vinblastine, vindecine,vincristine, vinorelbine; nucleoside derivatives and folic acidantagonists such as 5-fluorouracil, capecitabine, gemcitabine,mercaptopurine, thioguanine, cladribine, methotrexate; alkylatingagents, such as the nitrogen mustards, e.g., cyclophosphamide,chlorambucil, chiormethine, iphosphamide, melphalan, or thenitrosoureas, e.g., carmustine, lomustine, or other alkylating agents,e.g., busulphan, dacarbazine, procarbazine, thiotepa; antibiotics, suchas daunorubicin, doxorubicin, idarubicin, epirubicin, bleomycin,dactinomycin, mitomycin; HER 2antibody, such as trastuzumab;podophyllotoxin derivatives, such as etoposide, teniposide; famesyltransferase inhibitors; anthrachinon derivatives, such as mitoxantron);anti-migraine drugs (alniditan, naratriptan, sumatriptan);anti-Parkinsonian drugs (bromocryptine mesylate, levodopa, selegiline);antipsychotic, hypnotic, and sedating agents (alprazolam, buspirone,chlordiazepoxide, chlorpromazine, clozapine, diazepam, flupenthixol,fluphenazine, flurazepam, 9-hydroxyrisperidone, lorazepam, mazapertine,olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine,risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam,thiothixene, triazolam, trifluperidol, ziprasidone, zolpidem);anti-stroke agents (lubeluzole, lubeluzole oxide, riluzole, aptiganel,eliprodil, remacemide); antitussive (dextromethorphan,levodropropizine); antivirals (acyclovir, ganciclovir, loviride,tivirapine, zidovudine, lamivudine, zidovudine+lamivudine, didanosine,zalcitabine, stavudine, abacavir, lopinavir, amprenavir, nevirapine,efavirenz, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir,adefovir, hydroxyurea); beta-adrenoceptor blocking agents (atenolol,carvedilol, metoprolol, nebivolol, propanolol); cardiac inotropic agents(amrinone, digitoxin, digoxin, milrinone); corticosteroids(beclomethasone dipropionate, betamethasone, budesonide, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone); disinfectants (chlorhexidine); diuretics (acetazolamide,frusemide, hydrochlorothiazide, isosorbide); enzymes; essential oils(anethole, anise oil, caraway, cardamom, cassia oil, cineole, cinnamonoil, clove oil, coriander oil, dementholised mint oil, dill oil,eucalyptus oil, eugenol, ginger, lemon oil, mustard oil, neroli oil,nutmeg oil, orange oil, peppermint, sage, spearmint, terpineol, thyme);gastro-intestinal agents (cimetidine, cisapride, clebopride,diphenoxylate, domperidone, famotidine, lansoprazole, loperamide,loperamide oxide, mesalazine, metoclopramide, mosapride, nizatidine,norcisapride, olsalazine, omeprazole, pantoprazole, perprazole,prucalopride, rabeprazole, ranitidine, ridogrel, sulphasalazine);haemostatics (aminocaproic acid); lipid regulating agents (atorvastatin,lovastatin, pravastatin, probucol, simvastatin); local anaesthetics(benzocaine, lignocaine); opioid analgesics (buprenorphine, codeine,dextromoramide, dihydrocodeine, hydrocodone, oxycodone, morphine);parasympathomimetics and anti-dementia drugs (AIT-082, eptastigmine,galanthamine, metrifonate, milameline, neostigmine, physostigmine,tacrine, donepezil, rivastigmine, sabcomeline, talsaclidine, xanomeline,memantine, lazabemide); peptides and proteins (antibodies, becaplermin,cyclosporine, erythropoietin, immunoglobulins, insuline); sex hormones(oestrogens, conjugated oestrogens, ethinyloestradiol, mestranol,oestradiol, oestriol, oestrone; progestogens; chlormadinone acetate,cyproterone acetate, 17-deacetyl norgestimate, desogestrel, dienogest,dydrogesterone, ethynodiol diacetate, gestodene, 3-keto desogestrel,levonorgestrel, lynestrenol, medroxy-progesterone acetate, megestrol,norethindrone, norethindrone acetate, norethisterone, norethisteroneacetate, norethynodrel, norgestimate, norgestrel, norgestrienone,progesterone, quingestanol acetate); stimulating agents (sildenafil);vasodilators (amlodipine, buflomedil, amyl nitrite, diltiazem,dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine,molsidomine, nicardipine, nifedipine, oxpentifylline, pentaerythritoltetranitrate); their N-oxides, their pharmaceutically acceptable acid orbase addition salts and their stereochemically isomeric forms.

The following are non-limiting examples.

EXAMPLES

Preparation of Pterostilbene Cocrystals

Reagents: Pterostilbene was acquired from Aptuit Laurus Pty. Ltd.,India. Caffeine, carbamazepine, glutaric acid, and piperazine werepurchased from Sigma-Aldrich and used as received. All other chemicalswere purchased from various suppliers and used without furtherpurification. FIG. 1 shows XRPD patterns for pterostilbene Form I (102),caffeine (as-received) (104), carbamazepine (as-received) (106), andcocrystals 1 (Form I and II) and 2 (top to bottom) (108, 110, 112).

Techniques: The following techniques were used to prepare thepterostilbene cocrystals of the invention. Of the techniques describedbelow, generally speaking, grinding method was used for determiningcocrystal formation, while solvent based methods at ambient or elevatedtemperatures were used for scale-up and characterization, and vapordiffusion or slow evaporation was used to grow single crystals.

Grinding Method: A weighed amount of pterostilbene as the activepharmaceutical/nutraceutical ingredient (API) was transferred to amilling container (typically, agate). A coformer was added in 1:1 or 2:1(API:coformer) molar ratio. A small amount of solvent which may includenon-polar, polar aprotic, or polar aprotic (if specified) and an agatemilling ball were added to the container, which was then attached to aRetsch mill. The mixture was milled for approximately 20 minutes at 30Hz, although other pre-determined time periods and other frequencies arealso contemplated. Where noted, solids were scraped down sides of jarhalfway through the milling process. The resulting solids weretransferred to a clean vial and analyzed.

Solvent Based Method at Ambient Temperature: A mixture of pterostilbeneand a coformer was prepared in a given solvent by adding solids of onecomponent to a saturated (or near saturated) solution of the othercomponent. The solution was allowed to stir for an extendedpre-determined period of time. Any precipitated solids were isolated andanalyzed.

Solvent Based Method at Elevated Temperature: A solution ofpterostilbene and a coformer (in 1:1 or 2:1 API: coformer molar ratio)was prepared in a solvent or a solvent system with heating such that themixture is heated above ambient or room temperature. In some cases,solutions were filtered through a 0.2-μm nylon filter prior to cooling.Upon cooling to ambient temperature, solids were formed. The solids wereisolated and analyzed if specified. In some cases where sticky filmsresulted, the film was redissolved in a different solvent and theexperiment was repeated or other techniques were employed.

Vapor Diffusion: A concentrated solution of pterostilbene and a coformer(in 1:1 API: coformer molar ratio) was prepared in a solvent. Thesolution was dispensed into a small container, which was then placedinside a larger vessel containing antisolvent, which could include, butis not limited to, water. The small container was left uncapped and thelarger vessel was capped for a period of time to allow vapor diffusionto occur. Solids were isolated and analyzed, if indicated.

Slow Evaporation: A solution of pterostilbene and a coformer (in 1:1 or2:1 API: coformer molar ratio) was prepared in a solvent or solventsystem with agitation and/or gentle heating. The solution was allowed toevaporate at ambient conditions in a loosely covered vial. In somecases, solutions were filtered through a 0.2-μm nylon filter prior toevaporation. The solids were isolated and analyzed if specified.

Abbreviations: The following abbreviations are used in the examplesbelow:

EtOH ethanol

IPA isopropanol

EtOAc ethyl acetate

Example 1 Preparation of 1:1 Pterostilbene:Caffeine Cocrystal, 1 (FormI)

Cocrystal 1 (Form 1) was prepared by a grinding method and solvent-basedmethods. For grinding, a 1:1 mixture of pterostilbene (˜45 mg, ˜0.18mmol) and caffeine (˜34 mg, ˜0.18 mmol) were added to a milling jar.Approximately 25 μL of solvent (chloroform, acetonitrile, ethanol, ornitromethane) were added and the material was ground for 20 minutes at arate of 30 Hz. For the solvent-based methods at ambient temperature,solid caffeine was added to a nearly saturated solution of pterostilbenein ethanol and allowed to stir for ˜24 hours before filtering. Singlecrystals were grown from a vapor diffusion experiment where a 1:1mixture of pterostilbene (56.0 mg, 0.22 mmol) and caffeine (42.4 mg,0.22 mmol) was dissolved in a minimal amount of methanol (2 ml) in a 1dram vial. The 1 dram vial was placed uncapped in a 20 ml vialcontaining water. The larger vial was capped, and after 2 days,rod-shaped crystals were harvested.

Example 2 Preparation of 1:1 Pterostilbene:Caffeine Cocrystal, 1 (FormII)

Single crystals were grown from a vapor diffusion experiment where a 1:1mixture of pterostilbene (˜56.0 mg, ˜0.22 mmol) and caffeine (˜42.0 mg,˜0.22 mmol) was dissolved in a minimal amount of methanol (2 ml) in a 1dram vial. The 1 dram vial was placed uncapped in a 20 ml vialcontaining water. The larger vial was capped, and after 2 dayscolorless, prism-shaped crystals were harvested.

Example 3 Preparation of 1:1 Pterostilbene:Carbamazepine Cocrystal, 2

Cocrystal 2 was prepared by a grinding method and solvent-based methods.For grinding, a 1:1 mixture of pterostilbene (˜41 mg, ˜0.16 mmol) andcarbamazepine (˜38 mg, ˜0.16 mmol) was added to a milling jar.Approximately 25 μL of solvent (chloroform, acetonitrile, ethanol, orp-dioxane) were added and the material was ground for 20 minutes at arate of 30 Hz. The cocrystal was scaled up using solvent-based methodsat ambient temperature, where solid carbamazepine was added to a nearlysaturated solution of pterostilbene in toluene and allowed to stir for˜24 hours before filtering. Single crystals were grown from a vapordiffusion experiment where a 1:1 mixture of pterostilbene (55.3 mg, 0.22mmol) and carbamazepine (50.8 mg, 0.22 mmol) was dissolved in a minimalamount of methanol (2 ml) in a 1 dram vial. The 1 dram vial was placeduncapped in a 20 ml vial containing water. The larger vial was capped,and after 2 days, rod-shaped crystals were harvested.

Example 4 Preparation of 1:1 Pterostilbene:Glutaric Acid Cocrystal, 3

Pterostilbene:glutaric acid cocrystals were prepared by a grindingmethod, slow evaporation, or slow cooling. Utilizing grindingconditions, a 1:1 mixture of pterostilbene (˜36 mg, ˜0.14 mmol) andglutaric acid (˜19 mg, ˜0.14 mmol) was added to an agate milling jar.Approximately 10 μL of solvent (toluene or 2-propanol) were added andthe material ground for 20 minutes at a rate of 30 Hz. Using asolvent-based method at elevated temperature, the cocrystal was scaledup by dissolving a mixture of pterostilbene (3.03 g, 11.8 mmol) andglutaric acid (1.55 g, 11.7 mmol) in toluene (˜40 mL) with heat andallowing the solution to slowly cool. The homogeneous solution wasstirred, and, upon cooling, the solids precipitated. The white,crystalline solid was filtered and dried yielding 3.79 g, 83%. Singlecrystals were grown from slowly evaporating a 1:1 mixture ofpterostilbene (25.0 mg, 0.10 mmol) and glutaric acid (13.1 mg, 0.10mmol) in toluene (3 mL). After 1 day plate-shaped crystals wereharvested.

Example 5 Preparation of Pterostilbene:Piperazine Cocrystal, 4

Pterostilbene: piperazine cocrystals were prepared by a grinding method,slow evaporation, or slow cooling. For grinding conditions, a 2:1mixture of pterostilbene (˜65 mg, ˜0.25 mmol) and piperazine (˜11 mg,˜0.13 mmol) were added to an agate mill. Approximately 10 μL of solvent(ethanol or nitromethane) were added and the material ground for 20minutes at a rate of 30 Hz. Using a solvent-based method at elevatedtemperature, the cocrystal was scaled up by dissolving a mixture ofpterostilbene (5.12 g, 20.0 mmol) and piperazine (862 mg, 10.0 mmol) inethanol (˜70 mL) with heat. The solution was stirred in an oil bath forapproximately 1 h, upon which the heat was removed and solidsprecipitated. The white, crystalline solid was filtered and dried,yielding 10.54 g, 88%. Single crystals of cocrystal 4 were grown fromslowly evaporating a 1:1 mixture of pterostilbene (135.2 mg, 0.53 mmol)and piperazine (45.5 mg, 0.53 mmol) in ethanol (2 mL). After 1 dayrod-shaped crystals were harvested.

Characterization of Pterostilbene Cocrystals

Characterization Methods: The pterostilbene cocrystals of the presentinvention were characterized by X-ray powder diffraction, thermalgravimetric analysis, differential scanning calorimetry, single crystalX-ray diffraction, and solid state ¹³C NMR. Each method used isdescribed below. The stability (with respect to relative humidity) andsolubility of the pterostilbene cocrystals were also determined asdescribed below.

As used herein, the word “characterize” means to identify a collectionof data which may be used to identify a cocrystal of the invention. Theprocess by which cocrystals are characterized involves analyzing datacollected on the cocrystals so as to allow one of ordinary skill in theart to distinguish cocrystals of the same active pharmaceutical ornutraceutical ingredient. Chemical identity of cocrystals can often bedetermined with solution-state techniques such as ¹H NMR spectroscopywhich will provide or assist in providing the chemical identity of thecoformers as well as the API or active nutraceutical ingredient. Thus,such techniques can be used to differentiate and characterize cocrystalshaving different coformers but the same drug (or active nutraceuticalingredient).

One may also, for example, collect X-ray powder diffraction data oncocrystals such as cocrystals of pterostilbene. An X-ray powderdiffraction plot is an x-y graph with °2θ (diffraction angle) on thex-axis and intensity on the y-axis. The peaks within this plot may beused to characterize a crystalline solid form. The data is oftenrepresented by the position of the peaks on the x-axis rather than theintensity of peaks on the y-axis because peak intensity can beparticularly sensitive to sample orientation (see PharmaceuticalAnalysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is nottypically used by those skilled in the art to characterize solid formssuch as cocrystals. Indeed, those of ordinary skill in the art attemptto choose peaks which appear to be less influenced by preferredorientation to so as to make characterization more robust.

As with any data measurement, there is variability in X-ray powderdiffraction data. In addition to the variability in peak intensity,there is also variability in the position of peaks on the x-axis. Thisvariability can, however, typically be accounted for when reporting thepositions of peaks for purposes of characterization. Such variability inthe position of peaks along the x-axis derives from several sources. Onecomes from sample preparation. Samples of the same crystalline material,prepared under different conditions may yield slightly differentdiffractograms. Factors such as particle size, moisture content, solventcontent, and orientation may all affect how a sample diffracts X-rays.Another source of variability comes from instrument parameters.Different X-ray instruments operate using different parameters and thesemay lead to slightly different diffraction patterns from the samecrystalline solid form. Likewise, different software packages processX-ray data differently and this also leads to variability. These andother sources of variability are known to those of ordinary skill in thepharmaceutical arts.

Due to such sources of variability, it is common to recite X-raydiffraction peaks using the word “about” prior to the peak value in °2θwhich presents the data to within 0.1 or 0.2 °2θ of the stated peakvalue depending on the circumstances. The X-ray powder diffraction datacorresponding to the cocrystals of pterostilbene of the disclosure werecollected on instruments which were routinely calibrated and operated byskilled scientists. Accordingly, the variability associated with thesedata would be expected to be closer to ±0.1 °2θ and are so reportedherein.

For each cocrystal disclosed herein, peak lists for the XRPD patternsare presented in tabular form. Additionally, a subset of those peaklists was generated and identified as “representative” peaks.Representative peaks are selected from the generated peak list on theentire pattern by identifying peaks that are generally non-overlapping,at low angle, with relatively strong intensity, and for whichassessments of the affects of preferred orientation and particlestatistics on the peaks have been made.

For each of the cocrystals of pterostilbene of the invention, peak listsof the XRPD patterns as well as representative peaks were identified.For each cocrystal, characterization may be made by utilizing any one ofthe corresponding representative peaks, a collection of more than one ofthe peaks up to and including the entire representative peak list foreach cocrystal. Further, although not necessary to characterize aparticular cocrystal of pterostilbene, one may select the entirediffraction pattern to characterize the cocrystal.

X-ray Powder Diffraction (XRPD). Patterns were collected using aPANalytical X'Pert Pro or Inel XRG-3000 diffractometer. An incident beamof Cu Kα radiation was produced using an Optix long, fine-focus source.PANalytical data were collected and analysed using X'Pert Pro DataCollector software (v. 2.2b). Prior to the analysis, a silicon specimen(NIST SRM 640c) was analyzed to verify the Si 111 peak position.PANalytical diffraction patterns were collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thespecimen.

Thermogravimetric Analysis (TGA). Thermogravimetric analyses wereperformed using a TA Instruments 2050 thermogravimetric analyzer. Thesample was placed in an aluminum sample pan and inserted into the TGfurnace. Analysis began at ˜20° C., and the furnace was heated undernitrogen at a rate of 10 K/min, up to a final temperature of 350° C.Nickel and Alumel™ were used as calibration standards.

Differential Scanning calorimetry (DSC). DSC was performed using a TAInstruments 2920 differential scanning calorimeter. Temperaturecalibration was performed using NIST traceable indium metal. The samplewas placed into an aluminum DSC pan, and the weight was accuratelyrecorded. The pan was covered with a lid perforated with a laserpinhole, and the lid was crimped. A weighed, crimped aluminum pan wasplaced on the reference side of the cell. The sample cell wasequilibrated at 25° C. and heated under a nitrogen purge at a rate of 10K/min, up to a final temperature of 250° C. Differential Scanningcalorimetry data, like all thermal measurements, have variabilityassociated with measurements. In DSC, such variability may be a resultof pan configuration, heating rate, sample preparation, and colligativeproperties.

Single Crystal X-ray Diffraction (SCXRD). Datasets were collected on aBruker SMART APEX II (cocrystals 1, 3 and 4) and Kappa APEX II(cocrystal 2) using MoKα radiation. Data were collected using APEXIIsoftware. APEXII v1.27, © 2005, Bruker Analytical X-ray Systems,Madison, Wis. Initial cell constants were found by small widelyseparated “matrix” runs. Data collection strategies were determinedusing COSMO. Scan speed and scan width were chosen based on scatteringpower and peak rocking curves. All datasets were collected at −153° C.using an Oxford Cryostream low-temperature device.

Unit cell constants and orientation matrices were improved byleast-squares refinement of reflections thresholded from the entiredataset. Integration was performed with SAINT, (SAINT v6.02, ©1997-1999, Bruker Analytical X-ray Systems, Madison, Wis.) using thisimproved unit cell as a starting point. Precise unit cell constants werecalculated in SAINT from the final merged dataset. Lorenz andpolarization corrections were applied. Where indicated, absorptioncorrections were made using the multi-scan procedure in SADABS.

Data were reduced with SHELXTL (SHELXTL v5.10, © 1997, Bruker AnalyticalX-ray Systems, Madison, Wis.). The structures were solved in all casesby direct methods without incident. All hydrogens were assigned toidealized positions and were allowed to ride, except hydroxyl and ureaprotons.

Solid State ¹³C NMR Spectra. Solid state ¹³C NMR spectra were obtainedusing an Inova-400 spectrometer. The solid-state ¹³C cross polarizationmagic angle spinning (CP/MAS) NMR spectrum was acquired at ambienttemperature on a Varian ^(UNITY)INOVA-400 spectrometer (Larmorfrequencies: ¹³C=100.542 MHz, ¹H=399.799 MHz). The sample was packedinto a 4 mm PENCIL type zirconia rotor and rotated at 12 kHz at themagic angle. The spectrum was acquired with phase modulated (TPPM) highpower ¹H decoupling during the acquisition time using a ¹H pulse widthof 2.9 μs (90°), a ramped amplitude cross polarization contact time of 4ms, a 30 ms acquisition time, a 10 second delay between scans, aspectral width of 45 kHz with 2700 data points, and 100 co-added scans.The free induction decay (FID) was processed using Varian VNMR 6.1Csoftware with 32768 points and an exponential line broadening factor of10 Hz to improve the signal-to-noise ratio. The first three data pointsof the FID were back predicted using the VNMR linear predictionalgorithm to produce a flat baseline. The chemical shifts of thespectral peaks were externally referenced to the carbonyl carbonresonance of glycine at 176.5 ppm.

Example 6 Characterization of 1:1 Pterostilbene:Caffeine Cocrystal, 1(Form I)

Solids of cocrystal 1 (Form I) prepared by solvent-based conditionsaccording to Example 1 were used for characterization except that singlecrystals were grown by vapor diffusion, as described.

6.1 XRPD Characterization. The XRPD pattern of cocrystal 1 (Form I),obtained using a PANalytical X'Pert Pro diffractometer, is shown in FIG.2. Table 1 lists the peaks identified in the XRPD pattern of FIG. 2.Table 2 lists representative peaks from the XRPD pattern of FIG. 2. Therepresentative peaks in Table 2, or a subset of those peaks, as well asthe peaks in Table 1, or a subset of those peaks may be used tocharacterize cocrystal 1 (Form I).

TABLE 1 Cocrystal 1 (Form I). Intensity °2θ d space (Å) (%)  6.94 ± 0.1012.740 ± 0.186  6  9.45 ± 0.10 9.356 ± 0.100 92 10.08 ± 0.10 8.775 ±0.088 92 11.97 ± 0.10 7.395 ± 0.062 30 12.53 ± 0.10 7.066 ± 0.057 812.91 ± 0.10 6.856 ± 0.053 8 13.77 ± 0.10 6.430 ± 0.047 53 13.92 ± 0.106.364 ± 0.046 22 14.64 ± 0.10 6.050 ± 0.041 3 15.16 ± 0.10 5.844 ± 0.03928 16.02 ± 0.10 5.532 ± 0.035 12 16.43 ± 0.10 5.395 ± 0.033 8 16.81 ±0.10 5.273 ± 0.031 37 17.10 ± 0.10 5.186 ± 0.030 17 17.89 ± 0.10 4.958 ±0.028 3 18.72 ± 0.10 4.740 ± 0.025 13 18.99 ± 0.10 4.674 ± 0.025 1319.24 ± 0.10 4.614 ± 0.024 27 19.94 ± 0.10 4.453 ± 0.022 11 20.25 ± 0.104.386 ± 0.022 3 20.51 ± 0.10 4.331 ± 0.021 3 20.73 ± 0.10 4.284 ± 0.0214 21.28 ± 0.10 4.176 ± 0.019 8 21.84 ± 0.10 4.070 ± 0.018 24 22.43 ±0.10 3.964 ± 0.018 5 23.24 ± 0.10 3.827 ± 0.016 8 23.54 ± 0.10 3.779 ±0.016 5 23.95 ± 0.10 3.716 ± 0.015 7 24.39 ± 0.10 3.649 ± 0.015 6 24.70± 0.10 3.604 ± 0.014 6 25.20 ± 0.10 3.535 ± 0.014 8 25.97 ± 0.10 3.431 ±0.013 100 26.42 ± 0.10 3.373 ± 0.013 74 26.90 ± 0.10 3.314 ± 0.012 1027.16 ± 0.10 3.283 ± 0.012 6 27.70 ± 0.10 3.220 ± 0.011 5 27.92 ± 0.103.196 ± 0.011 8 28.33 ± 0.10 3.150 ± 0.011 11 28.59 ± 0.10 3.123 ± 0.0116

TABLE 2 Cocrystal 1 (Form I). °2θ d space (Å) Intensity (%)  9.45 ± 0.109.356 ± 0.100 92 10.08 ± 0.10 8.775 ± 0.088 92 13.77 ± 0.10 6.430 ±0.047 53 25.97 ± 0.10 3.431 ± 0.013 100 26.42 ± 0.10 3.373 ± 0.013 74

6.2 TGA and DSC Characterization. FIG. 3 shows the TGA and DSC tracesfor cocrystal 1 (Form I). As shown in FIG. 3, the melting point ofcocrystal 1 (Form I) is about 115° C. (114.33-115.59° C.). The tracesmay be used to characterize cocrystal 1 (Form I).

6.3 Single Crystal Characterization. FIG. 4 shows an ORTEP drawing ofcocrystal 1 (Form I). The complex crystallizes with two independentphenol/amine pairs per asymmetric unit. The two crystallographicallynonequivalent pairs were distinguished with use of the SHELXL “RESI”command. Coordinates for the phenol protons H31 (on each pterostilbene)were allowed to refine. The crystal structure and data refinementparameters are reported in Table 3.

TABLE 3 Cocrystal 1 (Form I). Empirical formula C24H26N4O5 Formulaweight 450.49 Temperature 120(2) K Wavelength 0.71073 Å Crystal systemMonoclinic Space group P2(1)/n Unit cell dimensions a = 17.4139(11) Å α= 90° b = 13.3693(8) Å β = 90.492(2)° c = 18.4844(10) Å γ = 90° Volume4303.2(4) Å³ Z 8 Density (calculated) 1.391 g/cm³ Absorption coefficient0.099 mm⁻¹ F(000) 1904 Crystal size 0.32 × 0.18 × 0.10 mm³ Theta rangefor data collection 1.60 to 33.14° Index ranges −25 <= h <= 17, −16 <= k<= 19, −27 <= l <= 28 Reflections collected 48373 Independentreflections 14776 [R(int) = 0.0428] Completeness to theta = 30.00° 99.2%Absorption correction None Max. and min. transmission 0.9902 and 0.9690Refinement method Full-matrix least-squares on F²Data/restraints/parameters 14776/0/611 Goodness-of-fit on F² 1.064 FinalR indices [I > 2sigma(I)] R1 = 0.0581, wR2 = 0.1606 R indices (all data)R1 = 0.0935, wR2 = 0.1833 Largest diff. peak and hole 0.620 and −0.309 e· Å⁻³

In the crystal structure shown in FIG. 4, the two-component assembliesare held together through an O—H•••O hydrogen bond from the hydroxylmoiety of pterostilbene to a carbonyl oxygen of caffeine. Hydrogen bondgeometries for cocrystals 1 (Forms I and II) and cocrystal 2 are shownin Table 4 below.

TABLE 4 Hydrogen-Bond Geometries for 1 (Form I and II) and 2 . . .θ(DHA)/ Cocrystal D-H•••A d(H•••A)/Å d(D•••A)/Å deg 1 (Form I)0311-H311•••O161 1.80(3) 2.7331(15) 168.9(18)  0312-H312•••O162 1.76(2)2.7112(15) 169.0(17)  1 0311-H311•••O161 1.80(3) 2.716(3) 175(3) (FormII) 0312-H312•••O162 1.96(3) 2.725(2) 169(3) 0313-H313•••O163 1.68(3)2.719(2) 174(3) 0314-H314•••O164 1.91(3) 2.716(3) 175(3) 2 041-H41•••O320.90(16)  2.736(13)  160(15) N31-H31A•••O32 0.88(17)  2.872(15)  174(15)

Cocrystals of caffeine are not uncommon, with the Cambridge StructuralDatabase (CSD v.5.31) listing 18 multi-component crystals where acarboxylic acid and/or hydroxyl moiety is present on the coformer andthe crystallographic coordinates are determined. Not surprising, basedon Etter's rules, when a carboxylic acid is present, the components areheld together through O13 H...N (caffeine) hydrogen bonds fifteen out ofeighteen times, while if carboxylic acid and hydroxyl moeities are bothpresent, O—H...O (caffeine) and/or O—H...N (caffeine) hydrogen bondsresult the three remaining times. The hydrogen bonding pattern ofcocrystal 1 was, therefore, unexpected since the O—H...N bond was notutilized, suggesting the energetics of the overall crystal packing arestronger than the hydrogen bonding interactions.

The cocrystal assemblies pack in two-dimensional sheets throughalternating rows of pterostilbene and caffeine molecules, while thestacked sheets result in a relatively planar arrangement inthree-dimensions, as shown in FIGS. 5A and 5B, respectively.

Example 7 Characterization of 1:1 Pterostilbene:Caffeine Cocrystal, 1(Form II)

Single crystals of cocrystal 1 (Form II) were grown by vapor diffusion,as reported in Example 2.

7.1 XRPD Characterization. The XRPD pattern of cocrystal 1 (Form II),obtained using a PANalytical X'Pert Pro diffractometer, is shown in FIG.6. Table 5 lists the peaks identified in the XRPD pattern of FIG. 6.Table 6 lists representative peaks from the XRPD pattern of FIG. 6. Therepresentative peaks in Table 6, or a subset of those peaks, as well asthe peaks in Table 5, or a subset of those peaks may be used tocharacterize cocrystal 1 (Form II).

TABLE 5 Cocrystal 1 (Form II). Intensity °2θ d space (Å) (%)  6.93 ±0.10 12.755 ± 0.187  3  9.45 ± 0.10 9.355 ± 0.100 23 10.07 ± 0.10 8.782± 0.088 20 10.57 ± 0.10 8.367 ± 0.080 4 11.96 ± 0.10 7.400 ± 0.062 312.56 ± 0.10 7.047 ± 0.056 3 12.90 ± 0.10 6.865 ± 0.053 2 13.80 ± 0.106.418 ± 0.047 16 13.90 ± 0.10 6.372 ± 0.046 14 14.17 ± 0.10 6.252 ±0.044 6 14.45 ± 0.10 6.130 ± 0.042 1 14.75 ± 0.10 6.005 ± 0.041 1 15.14± 0.10 5.854 ± 0.039 3 15.37 ± 0.10 5.765 ± 0.038 1 16.02 ± 0.10 5.532 ±0.035 4 16.41 ± 0.10 5.403 ± 0.033 3 16.81 ± 0.10 5.275 ± 0.031 12 17.09± 0.10 5.188 ± 0.030 2 18.70 ± 0.10 4.746 ± 0.025 3 18.98 ± 0.10 4.676 ±0.025 4 19.23 ± 0.10 4.616 ± 0.024 4 19.41 ± 0.10 4.572 ± 0.023 2 19.93± 0.10 4.455 ± 0.022 4 20.48 ± 0.10 4.336 ± 0.021 1 20.75 ± 0.10 4.281 ±0.021 1 21.25 ± 0.10 4.181 ± 0.020 1 21.82 ± 0.10 4.073 ± 0.019 5 22.37± 0.10 3.974 ± 0.018 2 23.22 ± 0.10 3.830 ± 0.016 2 23.54 ± 0.10 3.779 ±0.016 1 23.91 ± 0.10 3.722 ± 0.015 2 24.68 ± 0.10 3.608 ± 0.014 1 24.90± 0.10 3.577 ± 0.014 1 25.16 ± 0.10 3.539 ± 0.014 2 25.98 ± 0.10 3.430 ±0.013 100 26.45 ± 0.10 3.370 ± 0.013 24 26.90 ± 0.10 3.314 ± 0.012 327.15 ± 0.10 3.284 ± 0.012 2 28.32 ± 0.10 3.151 ± 0.011 4 29.54 ± 0.103.024 ± 0.010 2

TABLE 6 Cocrystal 1 (Form II). °2θ d space (Å) Intensity (%)  9.45 ±0.10 9.355 ± 0.100 23 10.07 ± 0.10 8.782 ± 0.088 20 25.98 ± 0.10 3.430 ±0.013 100 26.45 ± 0.10 3.370 ± 0.013 24

7.2 TGA and DSC Characterization. FIG. 7 shows the TGA and DSC tracesfor cocrystal 1 (Form II). As shown in FIG. 7, the melting point ofcocrystal 1 (Form II) is about 117° C. (115.81-118.07° C.). The tracesmay be used to characterize cocrystal 1 (Form II).

7.3 Single Crystal Characterization. FIG. 8 shows an ORTEP drawing ofcocrystal 1 (Form II). A small but significant degree of merohedraltwinning (emulating orthorhombic) was handled using appropriate TWIN andBASF commands. The structure was divided into four chemically identicalresidues by using the SHELXL “RESI” command. Each residue contained onepterostilbene and one caffeine molecule. Coordinates for the four uniquehydroxyl protons were allowed to refine. The crystal structure and datarefinement parameters are reported in Table 7.

TABLE 7 Cocrystal 1 (Form II). Empirical formula C24H26N4O5 Formulaweight 450.49 Temperature 120(2) K Wavelength 0.71073 Å Crystal systemMonoclinic Space group P2(1)/n Unit cell dimensions a = 17.424(2) Å α =90° b = 26.809(4) Å β = 90.225(5)° c = 18.546(2) Å γ = 90° Volume8663.1(18) Å³ Z 16 Density (calculated) 1.382 g/cm³ Absorptioncoefficient 0.098 mm⁻¹ F(000) 3808 Crystal size 0.25 × 0.20 × 0.15 mm³Theta range for data collection 0.76 to 32.03° Index ranges −22 <= h <=25, −35 <= k <= 39, −22 <= l <= 27 Reflections collected 99700Independent reflections 28191 [R(int) = 0.0655] Completeness to theta =27.50° 99.3% Absorption correction None Max. and min. transmission0.9854 and 0.9758 Refinement method Full-matrix least-squares on F²Data/restraints/parameters 28191/0/1222 Goodness-of-fit on F² 1.028Final R indices [I > 2sigma(I)] R1 = 0.0728, wR2 = 0.1796 R indices (alldata) R1 = 0.1316, wR2 = 0.2094 Largest diff. peak and hole 0.469 and−0.346 e · Å⁻³

As can be seen from the discussion above, crystalline Form I andcrystalline Form II of the pterostilbene:caffeine cocrystal 1 are notreadily distinguishable by X-ray powder diffraction. Although polymorphsof compounds are typically distinguished by X-ray powder diffraction,occasionally, that task is challenging with conventional powder X-raydiffractometers. Here applicants have shown that there are two forms bysingle-crystal X-ray diffraction. The single crystal structures of FormsI and II are nearly identical in 5 of the 6 parameters which define aunit cell (three lengths and three angles) and crystallize with the samespace group (P2(1)/n). One length, however, the “b” length differs insize between the two forms by a factor of two, making the unit cellvolume of the smaller polymorph (Form I) one-half that of Form II.Single-crystal measurements similarly indicate that Form I has eightpterostilbene:caffeine molecular pairs per unit cell whereas Form IIpossesses sixteen.

Accordingly, by using X-ray powder diffraction, applicants cancharacterize a genus of pterostilbene:caffeine polymorphs, the genusincluding the species of Form I and Form II of the cocrystal 1. By usingsingle-crystal X-ray powder analysis, applicants can distinguish andthus characterize either of Form I or Form II pterostilbene:caffeine. Itmay be possible to use other solid-state techniques to distinguish FormI from Form II of the pterostilbene:caffeine crystal 1.

Example 8 Characterization of Pterostilbene:Carbamazepine Cocrystal, 2

Solids of cocrystal 2 prepared by solvent-based conditions according toExample 3 were used for characterization except that single crystalswere grown by vapor diffusion, as described.

8.1 XRPD Characterization. The XRPD pattern of cocrystal 2, obtainedusing a PANalytical X'Pert Pro diffractometer, is shown in FIG. 9. Table8 lists the peaks identified in the XRPD pattern of FIG. 9. Table 9lists representative peaks from the XRPD pattern of FIG. 9. Therepresentative peaks in Table 9, or a subset of those peaks, as well asthe peaks in Table 8, or a subset of those peaks, may be used tocharacterize cocrystal 2.

TABLE 8 Cocrystal 2. °2θ d space (Å) Intensity (%)  5.04 ± 0.10 17.528 ±0.354  60 10.11 ± 0.10 8.754 ± 0.087 49 13.54 ± 0.10 6.540 ± 0.048 6313.64 ± 0.10 6.492 ± 0.048 62 14.88 ± 0.10 5.955 ± 0.040 77 15.19 ± 0.105.832 ± 0.038 17 15.70 ± 0.10 5.643 ± 0.036 26 16.56 ± 0.10 5.352 ±0.032 30 17.52 ± 0.10 5.061 ± 0.029 67 18.01 ± 0.10 4.926 ± 0.027 9118.13 ± 0.10 4.892 ± 0.027 97 18.49 ± 0.10 4.798 ± 0.026 22 19.20 ± 0.104.624 ± 0.024 83 19.84 ± 0.10 4.475 ± 0.022 50 20.31 ± 0.10 4.373 ±0.021 22 20.56 ± 0.10 4.320 ± 0.021 74 20.98 ± 0.10 4.234 ± 0.020 1121.39 ± 0.10 4.155 ± 0.019 25 21.80 ± 0.10 4.076 ± 0.019 78 22.40 ± 0.103.970 ± 0.018 31 22.91 ± 0.10 3.883 ± 0.017 87 23.27 ± 0.10 3.822 ±0.016 63 23.73 ± 0.10 3.749 ± 0.016 82 24.02 ± 0.10 3.705 ± 0.015 2325.12 ± 0.10 3.545 ± 0.014 11 25.47 ± 0.10 3.497 ± 0.014 15 25.89 ± 0.103.442 ± 0.013 68 26.51 ± 0.10 3.363 ± 0.013 47 26.92 ± 0.10 3.312 ±0.012 20 27.43 ± 0.10 3.252 ± 0.012 100 27.97 ± 0.10 3.190 ± 0.011 1228.50 ± 0.10 3.132 ± 0.011 20 28.80 ± 0.10 3.100 ± 0.011 29 29.09 ± 0.103.070 ± 0.010 21

TABLE 9 Cocrystal 2. °2θ d space (Å) Intensity (%)  5.04 ± 0.10 17.528 ±0.354  60 10.11 ± 0.10 8.754 ± 0.087 49 13.54 ± 0.10 6.540 ± 0.048 6313.64 ± 0.10 6.492 ± 0.048 62 14.88 ± 0.10 5.955 ± 0.040 77 17.52 ± 0.105.061 ± 0.029 67 18.01 ± 0.10 4.926 ± 0.027 91 18.13 ± 0.10 4.892 ±0.027 97 19.20 ± 0.10 4.622 ± 0.024 85 19.84 ± 0.10 4.475 ± 0.022 5020.56 ± 0.10 4.320 ± 0.021 74 21.80 ± 0.10 4.076 ± 0.019 78 22.91 ± 0.103.883 ± 0.017 87 23.27 ± 0.10 3.822 ± 0.016 63 23.73 ± 0.10 3.749 ±0.016 82 25.89 ± 0.10 3.442 ± 0.013 68 27.43 ± 0.10 3.252 ± 0.012 100

8.2 TGA and DSC Characterization. FIG. 10 shows the TGA and DSC tracesfor cocrystal 2. As shown in FIG. 10, the melting point of cocrystal 2is about 135° C. (134.01-135.53° C.). The traces may be used tocharacterize cocrystal 2.

8.3 Single Crystal Characterization. FIG. 11 shows an ORTEP drawing ofcocrystal 2. Coordinates for the urea protons and the hydroxyl protonwere allowed to refine. The crystal structure and data refinementparameters are reported in Table 10. Cocrystal 2 crystallizes in amonclinic C2/c space group with Z=8. The asymetric unit of cocrystal 2contains pterostilbene and carbamazepine in a 1:1 stoichiometric ratio

TABLE 10 Cocrystal 2. Empirical formula C31H28N2O4 Formula weight 492.55Temperature 120(2) K Wavelength 0.71073 Å Crystal system MonoclinicSpace group C2/c Unit cell dimensions a = 38.809(3) Å α = 90° b =5.3921(4) Å β = 117.306(3)° c = 26.7284(17) Å γ = 90° Volume 4969.9(6)Å³ Z 8 Density (calculated) 1.317 g/cm³ Absorption coefficient 0.087mm⁻¹ F(000) 2080 Crystal size 0.28 × 0.18 × 0.10 mm³ Theta range fordata collection 1.57 to 32.54° Index ranges −56 <= h <= 56, −7 <= k <=7, −39 <= l <= 40 Reflections collected 29297 Independent reflections8372 [R(int) = 0.0616] Completeness to theta = 30.00° 99.2% Absorptioncorrection None Max. and min. transmission 0.9913 and 0.9759 Refinementmethod Full-matrix least-squares on F² Data/restraints/parameters8372/0/345 Goodness-of-fit on F² 1.085 Final R indices [I > 2sigma(I)]R1 = 0.0515, wR2 = 0.1208 R indices (all data) R1 = 0.0882, wR2 = 0.1361Largest diff. peak and hole 0.386 and −0.256 e · Å⁻³

The components form a four-component supermolecule in whichcarbamazepine forms an amide:amide dimer through homomeric N—H...Ohydrogen bonds, while the pterostilbene is linked through O—H...Ohydrogen bonds from its hydroxyl group to the oxygen of the amide groupon carbamazepine, as shown in FIG. 12A. The anti-amino proton ofcarbamazepine is not engaged in hydrogen bonding. In three-dimensions,the carbamazepine molecules pack in a “translation stack” motif, asshown in FIG. 12B, which is one of the more common packing motifs formulti-component crystals containing carbamazepine.

Example 9 Characterization of Pterostilbene:Glutaric Acid Cocrystal, 3

Solids of cocrystal 3 prepared by slow cooling according to Example 4were used for characterization except that single crystals were grown byslow evaporation, as described.

9.1 XRPD Characterization. The XRPD pattern of cocrystal 3, obtainedusing a PANalytical X'Pert Pro diffractometer, is shown in FIG. 13.Table 11 lists the peaks identified in the XRPD pattern of FIG. 13.Table 12 lists representative peaks from the XRPD pattern of FIG. 13.The representative peaks in Table 12, or a subset of those peaks, aswell as the peaks in Table 11, or a subset of those peaks, may be usedto characterize cocrystal 3.

TABLE 11 Cocrystal 3. °2θ d space (Å) Intensity (%)  5.34 ± 0.10 16.560± 0.316  14 12.20 ± 0.10 7.252 ± 0.060 25 12.51 ± 0.10 7.078 ± 0.057 713.32 ± 0.10 6.645 ± 0.050 23 14.61 ± 0.10 6.063 ± 0.042 5 15.76 ± 0.105.622 ± 0.036 9 16.25 ± 0.10 5.455 ± 0.034 23 16.43 ± 0.10 5.394 ± 0.0338 17.15 ± 0.10 5.170 ± 0.030 6 17.50 ± 0.10 5.067 ± 0.029 10 18.89 ±0.10 4.698 ± 0.025 5 19.32 ± 0.10 4.593 ± 0.024 21 19.64 ± 0.10 4.520 ±0.023 11 20.09 ± 0.10 4.419 ± 0.022 8 20.54 ± 0.10 4.323 ± 0.021 6 21.45± 0.10 4.143 ± 0.019 13 21.66 ± 0.10 4.102 ± 0.019 26 21.96 ± 0.10 4.047± 0.018 6 22.23 ± 0.10 3.999 ± 0.018 4 22.73 ± 0.10 3.912 ± 0.017 523.05 ± 0.10 3.859 ± 0.017 3 23.43 ± 0.10 3.796 ± 0.016 7 24.02 ± 0.103.705 ± 0.015 10 24.45 ± 0.10 3.640 ± 0.015 8 25.16 ± 0.10 3.540 ± 0.0145 25.42 ± 0.10 3.504 ± 0.014 7 25.76 ± 0.10 3.459 ± 0.013 100 25.91 ±0.10 3.439 ± 0.013 98 26.33 ± 0.10 3.385 ± 0.013 16 27.30 ± 0.10 3.267 ±0.012 11 29.47 ± 0.10 3.031 ± 0.010 2

TABLE 12 Cocrystal 3. °2θ d space (Å) Intensity (%) 12.20 ± 0.10 7.252 ±0.060 25 13.32 ± 0.10 6.645 ± 0.050 23 16.25 ± 0.10 5.455 ± 0.034 2319.32 ± 0.10 4.593 ± 0.024 21 21.66 ± 0.10 4.102 ± 0.019 26 25.76 ± 0.103.459 ± 0.013 100 25.91 ± 0.10 3.439 ± 0.013 98

9.2 Single Crystal Characterization. FIG. 14 shows an ORTEP drawing ofcocrystal 3. Coordinates for the carboxylic acid protons H11 and H15 andthe phenol proton H21 were allowed to refine. The crystal structure anddata refinement parameters are reported in Table 13.

TABLE 13 Cocrystal 3. Empirical formula C21H24O7 Formula weight 388.40Temperature 120(2) K Wavelength 0.71073 Å Crystal system MonoclinicSpace group P2(1)/c Unit cell dimensions a = 7.2644(3) Å α = 90° b =32.8801(16) Å β = 96.000(2)° c = 7.9819(4) Å γ = 90° Volume 1896.07(15)Å³ Z 4 Density (calculated) 1.361 g/cm³ Absorption coefficient 0.102mm⁻¹ F(000) 824 Crystal size 0.26 × 0.14 × 0.08 mm³ Theta range for datacollection 1.24 to 32.58° Index ranges −11 <= h <= 6, −49 <= k <= 49,−11 <= l <= 12 Reflections collected 30177 Independent reflections 6677[R(int) = 0.0280] Completeness to theta = 32.58° 96.9% Absorptioncorrection None Max. and min. transmission 0.9919 and 0.9739 Refinementmethod Full-matrix least-squares on F² Data/restraints/parameters6677/0/262 Goodness-of-fit on F² 1.086 Final R indices [I > 2sigma(I)]R1 = 0.0472, wR2 = 0.1224 R indices (all data) R1 = 0.0660, wR2 = 0.1396Largest diff. peak and hole 0.570 and −0.254 e · Å⁻³

9.3 Solid State ¹³C NMR Characterization. FIG. 15 shows the solid state¹³C NMR spectrum of cocrystal 3. The solid state ¹³C NMR spectra ofpterostilbene and glutaric acid are shown in FIGS. 16 and 17,respectively. The spectrum may be used to characterize cocrystal 3.

Example 10 Characterization of Pterostilbene:Piperazine Cocrystal, 4

Solids of cocrystal 4 prepared by slow cooling according to Example 5were used for characterization except that single crystals were grown byslow evaporation, as described.

10.1 XRPD Characterization. The XRPD pattern of cocrystal 4, obtainedusing a PANalytical X'Pert Pro diffractometer, is shown in FIG. 18.Table 14 lists the peaks identified in the XRPD pattern of FIG. 18.Table 15 lists representative peaks from the XRPD pattern of FIG. 18.The representative peaks in Table 15, or a subset of those peaks, aswell as the peaks in Table 14, or a subset of those peaks may be used tocharacterize cocrystal 4.

TABLE 14 Cocrystal 4. °2θ d space (Å) Intensity (%)  3.42 ± 0.10 25.829± 0.778  12  7.63 ± 0.10 11.584 ± 0.154  12  9.05 ± 0.10 9.769 ± 0.10912 10.29 ± 0.10 8.598 ± 0.084 9 11.38 ± 0.10 7.779 ± 0.069 8 13.75 ±0.10 6.441 ± 0.047 10 14.15 ± 0.10 6.259 ± 0.044 12 14.93 ± 0.10 5.932 ±0.040 57 15.34 ± 0.10 5.778 ± 0.038 30 15.80 ± 0.10 5.608 ± 0.035 1216.86 ± 0.10 5.260 ± 0.031 6 17.26 ± 0.10 5.138 ± 0.030 31 18.11 ± 0.104.898 ± 0.027 19 18.43 ± 0.10 4.815 ± 0.026 40 18.68 ± 0.10 4.751 ±0.025 13 19.08 ± 0.10 4.652 ± 0.024 36 19.61 ± 0.10 4.526 ± 0.023 4420.33 ± 0.10 4.368 ± 0.021 34 21.10 ± 0.10 4.210 ± 0.020 4 21.74 ± 0.104.089 ± 0.019 7 21.99 ± 0.10 4.043 ± 0.018 6 22.57 ± 0.10 3.939 ± 0.01746 22.77 ± 0.10 3.905 ± 0.017 100 23.11 ± 0.10 3.849 ± 0.017 29 23.56 ±0.10 3.777 ± 0.016 62 24.13 ± 0.10 3.689 ± 0.015 32 24.81 ± 0.10 3.589 ±0.014 15 25.40 ± 0.10 3.507 ± 0.014 6 25.60 ± 0.10 3.480 ± 0.013 9 26.47± 0.10 3.368 ± 0.013 11 26.73 ± 0.10 3.335 ± 0.012 4 27.42 ± 0.10 3.253± 0.012 13 27.75 ± 0.10 3.215 ± 0.011 4 28.24 ± 0.10 3.161 ± 0.011 1528.39 ± 0.10 3.144 ± 0.011 51 28.65 ± 0.10 3.115 ± 0.011 17 29.51 ± 0.103.027 ± 0.010 17

TABLE 15 Cocrystal 4. °2θ d space (Å) Intensity (%) 14.93 ± 0.10 5.932 ±0.040 57 18.43 ± 0.10 4.815 ± 0.026 40 19.08 ± 0.10 4.652 ± 0.024 3619.61 ± 0.10 4.526 ± 0.023 44 20.33 ± 0.10 4.368 ± 0.021 34 22.57 ± 0.103.939 ± 0.017 46 22.77 ± 0.10 3.905 ± 0.017 100 23.56 ± 0.10 3.777 ±0.016 62 24.13 ± 0.10 3.689 ± 0.015 32 28.39 ± 0.10 3.144 ± 0.011 51

10.2 TGA and DSC Characterization. FIG. 19 shows the TGA and DSC tracesfor cocrystal 4. As shown in FIG. 19, the melting point of cocrystal 4is about 133° C. (130.98-135.59° C.). The traces may be used tocharacterize cocrystal 4.

10.3 Single Crystal Characterization. FIG. 20 shows an ORTEP drawing ofcocrystal 4. The two crystallographically nonequivalent pterostilbeneswere distinguished with use of the SHELXL “RESI” command. The compoundcrystallizes in the noncentrosymmetric space group P2₁2₁2₁. Due to theabsence of heavy atom anomalous scatterers, determination of crystalhandedness was not pursued, and Friedel oppposites were merged.Coordinates for the amine protons H11 & H14 and phenol protons H21 (oneach pterostilbene) were allowed to refine. An extinction correction wasapplied; the EXTI parameter refined to a small but non-zero number. Thecrystal structure and data refinement parameters are reported in Table16.

TABLE 16 Cocrystal 4. Empirical formula C36H42N2O6 Formula weight 598.72Temperature 296(2) K Wavelength 0.71073 Å Crystal system OrthorhombicSpace group P2(1)2(1)2(1) Unit cell dimensions a = 5.2586(7) Å α = 90° b= 11.7922(14) Å β = 90° c = 51.155(7) Å γ = 90° Volume 3172.2(7) Å³ Z 4Density (calculated) 1.254 g/cm³ Absorption coefficient 0.085 mm⁻¹F(000) 1280 Crystal size 0.36 × 0.10 × 0.04 mm³ Theta range for datacollection 1.77 to 27.57° Index ranges −6 <= h <= 4, −15 <= k <= 11, −66<= l <= 66 Reflections collected 37364 Independent reflections 4250[R(int) = 0.0955] Completeness to theta = 27.57° 99.5% Absorptioncorrection None Max. and min. transmission 0.9966 and 0.9700 Refinementmethod Full-matrix least-squares on F² Data/restraints/parameters4250/0/414 Goodness-of-fit on F² 0.967 Final R indices [I > 2sigma(I)]R1 = 0.0545, wR2 = 0.0948 R indices (all data) R1 = 0.1713, wR2 = 0.1255Absolute structure parameter 0(2) Extinction coefficient 0.0095(9)Largest diff. peak and hole 0.147 and −0.166 e · Å⁻³

Example 11 Equilbrium Solubility of Pterostilbene:CarbamazepineCocrystal 2 and Powder Dissolution of Pterostilbene:Caffeine Cocrystal 1(Form I)

Solubility and concentration measurements were performed usingultraviolet (UV) spectroscopy on a Spectramax Microplate Reader. Forcarbamazepine and caffeine, standard curves were produced by serialdilutions; absorbance readings at 275 or 284 nm for caffeine orcarbamazepine, respectively, were used to establish a linear regression.The small amount of methanol used to prepare carbamazepine standards didnot cause shifting in the absorbance spectrum.

Caffeine, carbamazepine, and cocrystal 2 were slurried in water for 72hours, filtered through a 0.2 μm nylon filter, and analyzed via a96-well quartz plate in duplicate. Cocrystal 1 (Form I) was slurried inwater, and aliquots were taken at specific time points to derive aconcentration versus time profile to estimate the maximum concentrationbefore transformation to pterostilbene occurred. Appropriate dilutionswith water were made as necessary to maintain absorbance readings withinthe standard curve. All experiments were repeated three times toevaluate the standard deviation, while particle size was not controlledfor any of the experiments. The equilibrium solubility measurement ofpterostilbene Form I was determined by HPLC. The concentration atapproximately 5 hours for cocrystal 1 (Form I) was 33 times lowercompared to the solubility of caffeine hydrate, but was 27 times higherthan pterostilbene's aqueous solubility. Cocrystal 2 showed a 7- and2.5-fold decrease in solubility in comparison to carbamazepine andpterostilbene, respectively. The solubility measurements are reported inTable 17. FIG. 21 shows a concentration vs. time profile for cocrystal 1(Form I) and equilibrium solubility of pterostilbene at ambienttemperature.

TABLE 17 Solubility Data. Compounds Solubility (±standard deviation)(μg/mL) pterostilbene 21^(a) caffeine 18.5 (±0.5) × 10³ carbamazepine 56± 4  cocrystal 2 8.5 ± 0.7 cocrystal 1 (Form I) 560 ± 9^(b)   ^(a)FormI, PCT/US2010/22285 ^(b)concentration measurement at ~5 hours

Example 12 Relative Humidity Stability of Pterostilbene, Caffeine,Carbamazepine, Cocrystal 1 (Form I), and Cocrystal 2

The conversion between an anhydrate and hydrate (or vice versa) can bevery problematic during the drug development process. One potentialconcern is a change in crystal form as a function of atmospherichumidity, which could lead to significantly different physicochemicalproperties between forms. Caffeine and carbamazepine are known toconvert to a non-stoichiometric hydrate or dihydrate, respectively, atelevated humdity levels. Not suprising, the aqueous solubilities of thehydrate/anhydrate forms are considerably different. It has beenpreviously shown that physical stability of APIs, known to convert totheir respected hydrated forms, can be improved through cocrystalformation. Thus, cocrystals 1 and 2 are good candidates for a systematicstudy assessing the effects of increased RH in comparison to caffeineand carbamazepine.

Relative humidity (RH) conditions were created at ambient temperaturesusing saturated salt solutions: NaCl ˜75%, KNO₃ ˜94%, and K₂SO₄ ˜98%.Vials of each sample containing approximately 10 mg, were subjected tophysical stability at ˜75% RH, ˜94% RH, and ˜98% RH for one day, threedays, one week, and four weeks within a closed chamber. Pterostilbenewas stressed at ˜75% RH, ˜94% RH, and ˜98% RH for four weeks. Uponcompletion of the duration allowed, the samples were immediatelyanalyzed by XRPD. The results are reported in Table 19.

TABLE 19 Stability Data. Stressed Material Conditions, Time^(a) Resultspterostilbene 75% RH, 4 weeks pterostilbene (Form I) (Form I) only 94%RH, 4 weeks pterostilbene (Form I) 98% RH, 4 weeks pterostilbene (FormI) caffeine only 75% RH, 1 day caffeine anhydrous 75% RH, 3 dayscaffeine anhydrous 75% RH, 1 week caffeine anhydrous 75% RH, 4 weekscaffeine anhydrous 94% RH, 1 day caffeine anhydrous 94% RH, 3 dayscaffeine anhydrous/caffeine hydrate 94% RH, 1 week caffeine hydrate 94%RH, 4 weeks caffeine hydrate 98% RH, 1 day caffeine hydrate 98% RH, 3days caffeine hydrate 98% RH, 1 week caffeine hydrate 98% RH, 4 weekscaffeine hydrate cocrystal 1 75% RH, 1 day cocrystal 1 (Form I), nocaffeine hydrate (Form I) additional stress at cocrystal 1 (Form I), nocaffeine hydrate 98% RH, 1 day 75% RH, 3 days cocrystal 1 (Form I), nocaffeine hydrate 75% RH, 1 week cocrystal 1 (Form I), no caffeinehydrate additional stress at cocrystal 1 (Form I), no caffeine hydrate98% RH, 1 week 75% RH, 4 weeks cocrystal 1 (Form I), no caffeine hydrate94% RH, 1 day cocrystal 1 (Form I), no caffeine hydrate additionalstress at — 98% RH, 3 days 94% RH, 3 days cocrystal 1 (Form I), nocaffeine hydrate 94% RH, 7 days cocrystal 1 (Form I), no caffeinehydrate additional stress at cocrystal 1 (Form I), no caffeine hydrate98% RH, 4 weeks 94% RH, 4 weeks cocrystal 1 (Form I), no caffeinehydrate slurry, 2 days cocrystal 1 (Form I), no caffeine hydratecarbamazepine only 75% RH, 1 day carbamazepine (Form III) 75% RH, 3 dayscarbamazepine (Form III) 75% RH, 1 week carbamazepine (Form III) 75% RH,4 weeks carbamazepine (Form III) 94% RH, 1 day carbamazepine (Form III)94% RH, 3 days carbamazepine (Form III) 94% RH, 1 week carbamazepine(Form III) + small amount of dihydrate 94% RH, 4 weeks carbamazepinedihydrate + small amount of carbamazepine (Form III) 98% RH, 1 daycarbamazepine (Form III) + small amount of dihydrate 98% RH, 3 dayscarbamazepine (Form III) + small amount of dihydrate 98% RH, 1 weekcarbamazepine dihydrate + small amount of carbamazepine (Form III) 98%RH, 4 weeks carbamazepine dihydrate cocrystal 2 75% RH, 1 day cocrystal2, no carbamazepine dihydrate 75% RH, 3 days cocrystal 2, nocarbamazepine dihydrate 75% RH, 1 week cocrystal 2, no carbamazepinedihydrate 75% RH, 4 weeks cocrystal 2, no carbamazepine dihydrate 94%RH, 1 day cocrystal 2, no carbamazepine dihydrate 94% RH, 3 dayscocrystal 2, no carbamazepine dihydrate 94% RH, 1 week cocrystal 2, nocarbamazepine dihydrate 94% RH, 4 weeks cocrystal 2, no carbamazepinedihydrate 98% RH, 1 day cocrystal 2, no carbamazepine dihydrate 98% RH,3 days cocrystal 2, no carbamazepine dihydrate 98% RH, 1 week cocrystal2, no carbamazepine dihydrate 98% RH, 4 weeks cocrystal 2, nocarbamazepine dihydrate ^(a)All % RH conditions and stressing times areapproximate.

As noted above, caffeine does not display signs of conversion at 75% RHup to four weeks; however, between one and three days at 94% RH partialconversion is observed, while at 98% RH anhydrous caffeine converts tocaffeine hydrate in less than one day. In comparision, cocrystal 1showed remarkable physical stability displaying no dissociation at 75,94, or 98% RH after four weeks by XRPD. Carbamazepine shows similarhydration patterns to caffeine, in that no conversion is observed at 75%RH, while at 94% RH anhydrous carbamazepine partially converts to thedihydrate between three days and one week. Full conversion to thedihydrate is observed in less than one day at 98% RH. Once again,pterostilbene improves the physical stability of caffeine, as observedby no dissociation of cocrystal 3 into its individual components at 75,94, or 98% RH after four weeks.

Example 13 Physical Stability of Pterostilbene:Glutaric Acid Cocrystal 3and Pterostilbene:Piperazine Cocrystal 4

Physical stability was evaluated at approximately 40° C., 60° C., 25°C./75% RH, 25° C./98% RH, and 40° C./75% RH and XRPD was used to detectdissociation or form conversion. Vials of each cocrystal were subjectedto each condition for durations of two weeks, one month, and two months.Upon completion of the duration allowed, the samples were immediatelyanalyzed by XRPD. The results are reported in Table 20.

TABLE 20 Stability Data. Stressed Material Conditions, Time^(a) Results(by XRPD) cocrystal 3 40° C., 2 weeks cocrystal 3 40° C., 4 weekscocrystal 3 40° C., 8 weeks cocrystal 3 60° C., 2 weeks cocrystal 3 60°C., 4 weeks cocrystal 3 60° C., 8 weeks cocrystal 3 25° C./75% RH, 2weeks cocrystal 3 25° C./75% RH, 4 weeks cocrystal 3 25° C./75% RH, 8weeks cocrystal 3 25° C./98% RH, 2 weeks cocrystal 3 25° C./98% RH, 4weeks cocrystal 3 25° C./98% RH, 8 weeks cocrystal 3 40° C./75% RH, 2weeks cocrystal 3 40° C./75% RH, 4 weeks cocrystal 3 40° C./75% RH, 8weeks cocrystal 3 cocrystal 4 40° C., 2 weeks cocrystal 4 40° C., 4weeks cocrystal 4 40° C., 8 weeks cocrystal 4 60° C., 2 weeks cocrystal4 60° C., 4 weeks cocrystal 4 60° C., 8 weeks cocrystal 4 25° C./75% RH,2 weeks cocrystal 4 25° C./75% RH, 4 weeks cocrystal 4 25° C./75% RH, 8weeks cocrystal 4 25° C./98% RH, 2 weeks cocrystal 4 25° C./98% RH, 4weeks cocrystal 4 25° C./98% RH, 8 weeks cocrystal 4 40° C./75% RH, 2weeks cocrystal 4 40° C./75% RH, 4 weeks cocrystal 4 40° C./75% RH, 8weeks cocrystal 4 ^(a)All % RH conditions and stressing times areapproximate.

Example 14 Powder Dissolution of Pterostilbene:Piperazine Cocrystal 4and attempted Pterostilbene:Glutaric Acid Cocrystal 3

Concentration measurements were performed using ultraviolet (UV)spectroscopy on a Spectramax Microplate Reader. For pterostilbene, astandard curve was produced by serial dilutions; absorbance readings at315 nm for pterostilbene were used to establish a linear regression. Thesmall amount of methanol used to prepare pterostilbene standards did notcause shifting in the absorbance spectrum.

Cocrystal 4 was slurried in water at ambient, and aliquots were taken atspecific time points to derive a concentration versus time profile toestimate the maximum concentration before transformation topterostilbene occurred. Aliquots were centrifuged; supernatant wasextracted, and appropriate dilutions were made to maintain absorbancereadings within the standard curve. Absorbance measurements were takenat 315 nm for pterostilbene, and concentrations were calculated from thestandard curve. All experiments were repeated three times to evaluatethe standard deviation, while particle size was not controlled for anyof the experiments. The concentration measurement at approximately fivehours for cocrystal 4 is reported in Table 21.

TABLE 21 Solubility Data. Compounds Solubility (±standard deviation)μg/mL) pterostilbene 21^(a) cocrystal 4 123 ± 6^(b) ^(a)Form I,PCT/US/2010/22285 ^(b)concentration measurement at ~5 hours

Attempted Powder and Intrinsic Dissolution of Pterostilbene:GlutaricAcid Cocrystal.

Powder dissolution of cocrystal 3 was attempted under the sameexperimental conditions as the cocrystal 4. However, XRPD resultsindicate crystalline pterostilbene after 5 minutes when slurrying inwater at ambient. Intrinsic dissolution in 900 mL water at ambientconditions was also attempted. However, XRPD results indicatecrystalline pterostilbene after 30 minutes. Therefore, a concentrationvs. time and intrinsic dissolution rate value were unobtainable at theseconditions. However, due to crystalline pterostilbene being the onlyproduct observed by XRPD after slurrying in water, we can conclude thesolubility of cocrystal 3 is greater than the solubility ofpterostilbene.

Although certain presently preferred embodiments of the disclosedinvention have been specifically described herein, it will be apparentto those skilled in the art to which the invention pertains thatvariations and modifications of the various embodiments shown anddescribed herein may be made without departing from the spirit and scopeof the invention. For example, the invention contemplates thepossibility of the presence of at least some hydrated or solvatedcocrystals, free API or free coformers in the crystalline structures.Accordingly, it is intended that the invention be limited only to theextent required by the appended claims and the applicable rules of law.

1. A pterostilbene:piperazine cocrystal.
 2. The cocrystal according toclaim 1, wherein the molar ratio of pterostilbene: piperazine is 2:1. 3.The cocrystal according to claim 1 having unique peaks at about 14.93,18.43, 19.08, 19.61, 20.33, 22.57, 22.77, 23.56, 24.13, and 28.39degrees two theta (±0.10 degrees) when analyzed by powder X-raydiffraction using Cu K-alpha radiation.
 4. The cocrystal according toclaim 1 having the powder X-ray diffraction pattern shown in FIG.
 18. 5.A pterostilbene:piperazine cocrystal having a solid phase melting pointat about 135° C. measured by DSC.
 6. A composition comprising: an amountof pterostilbene:piperazine cocrystals; and one or more excipients. 7.The composition according to claim 6, wherein the one or more excipientsis one or more of a binder, filler, lubricant, emulsifier, suspendingagent, sweetener, flavoring, preservative, buffer, wetting agent,disintegrant, effervescent agent, additive, and mixtures thereof.
 8. Thecomposition according to claim 7, wherein the additive is selected fromthe group consisting of microcrystalline cellulose, lactose, sucrose,fructose, glucose, dextrose, di-basic calcium phosphate, calciumsulfate, cellulose, methylcellulose, cellulose derivatives, kaolin,mannitol, lactitol, maltitol, xylitol, sorbitol, sugar alcohols, drystarch, dextrin, maltodextrin, polysaccharides, and mixtures thereof. 9.The composition according to claim 6, further comprising one or morepharmaceutically acceptable carriers, pharmaceutically acceptableexcipients, medicinal agents, pharmaceutical agents, adjuvants,diluents, and mixtures thereof.
 10. A pharmaceutical or nutraceuticaldosage form comprising the cocrystal according to claim
 1. 11. Thedosage form according to claim 10, wherein the dosage form is an oraldosage form selected from the group consisting of a tablet, capsule,powder, suspension and lozenge.
 12. The dosage form according to claim11, wherein the dosage form comprises a coated or uncoated tabletcomprising one or more of a release modifying agent, glidant,compression aid, disintegrant, effervescent agent, lubricant, binder,diluent, flavor, flavor enhancer, sweetener, and preservative.
 13. Amethod of making a pterostilbene:piperazine cocrystal comprising: addinga pre-determined amount of solid pterostilbene and solid piperazine in avessel; and grinding the mixture for a pre-determined period of time.14. The method according to claim 13, further comprising the step ofadding a suitable solvent to the vessel.
 15. The method according toclaim 14, wherein the solvent is selected from one of ethanol andnitromethane.
 16. A method of making a pterostilbene:piperazinecocrystal comprising: to a solution having pterostilbene dissolved in asuitable solvent, mixing an amount of piperazine for a pre-determinedperiod of time, or to a solution of piperazine dissolved in a suitablesolvent, mixing an amount of pterostilbene for a pre-determined periodof time; and isolating the solids.
 17. The method according to claim 16,wherein the step of isolating involves filtering the mixture.
 18. Themethod according to claim 16, wherein the step of mixing is conducted ata temperature above room temperature.
 19. The method according to claim16, further comprising cooling the mixture before isolating thecocrystals.
 20. The method according to claim 16, where the suitablesolvent is ethanol.
 21. A method of making a pterostilbene:piperazinecocrystal comprising: in a first vessel containing a suitable solvent,dissolving an amount of pterostilbene and an amount of piperazine;optionally agitating or heating the mixture for a pre-determined timeperiod; and isolating the cocrystals.
 22. The method according to claim21, wherein the suitable solvent is ethanol.
 23. The method according toclaim 21, further comprising the step of: placing the first vesselinside a second vessel having a suitable antisolvent for apre-determined period of time.
 24. The method according to claim 23,wherein the suitable antisolvent is water.